Can an enzyme's catalytic properties be reproduced by constructing in a smaller molecule the exact topography of an enzyme's active site? Designing, synthesizing, and studying the reaction dynamics of molecules that model the Asp-His hydrogen bond found in serine protease active sites is the aim of this research. Specifically, the goal is to test the hypothesis that the orientation of carboxyl(ate) is an important factor in its hydrogen bonding to an imidazole. Serine proteases form an important family of enzymes whose members are essential to a variety of physiological functions: digestion, blood coagulation, lysis of blood clots, and sperm penetration. These enzymes possess a common structural feature in their active sites known as the "charge-relay chain". Previous chemical models have neglected the orientation of the carboxylate in the Asp-His part of the chain. The carboxylate orientation hypothesis states that hydrogen bonding or complete proton transfer to carboxylate is more favored in a syn arrangement than an anti. For the serine protease enzymes, this applies to the Asp-His hydrogen bond. Crystallographic evidence from the enzymes reveals the carboxylate to be oriented syn in all cases. Surprisingly all the reported chemical models of this interaction have the carboxylate oriented anti. The proposal describes the preparation of the first models in which the carboxylate is oriented syn in a hydrogen bonding interaction with imidazole. The utility of chemical models to biomedicine is well recognized. What is there about this proposal that distinguishes it from other model studies? There are three distinguishing features: the testing of an hypothesis, the design approach and the emphasis on optimizing functional group topography.